Immune cells in the brain die to prevent infections from damaging the brain

Breaking new ground 9. mar 2021 3 min Associate Professor Line Reinert Written by Kristian Sjøgren

When a viral infection develops in the brain, the immune response can be so strong that it damages the brain. Danish researchers have discovered that immune cells in the brain die through apoptosis to minimize the excessive immune response.

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Not very long ago, researchers thought that the brain does not need an immune response to protect itself against viruses and bacteria.

However, this turned out to be incorrect, because the brain has a neuroimmune system separate from the immune system in the rest of the body, and researchers are trying to understand this.

Now Danish researchers have discovered how the neuroimmune system responds to a viral infection and what it does to protect the brain when the brain overreacts to an external threat.

“Viruses such as herpes simplex virus type 1 (HSV-1) can enter the brain and cause viral encephalitis among people such as those with congenitally weakened immune systems and those who are older. However, we have known very little about how the neuroimmune system defends the brain against viral infections, and this is important for understanding how to treat encephalitis or to help the immune response to combat an infection. However, we now know much more about this,” explains co-author Line Reinert, Associate Professor, Department of Biomedicine, Aarhus University.

The results, based on research in Søren Paludan’s laboratory , have been published in the Journal of Clinical Investigation.

The neuroimmune system

Understanding the neuroimmune system requires understanding that a virus enters the brain by infecting peripheral sensory neurons and how the virus replicates in neurons.

The virus induces the neurons to produce many new viruses, which are released into the brain microenvironment and can then infect new neurons. This activates the neuroimmune system, comprising various immune cells, including microglia, that patrol the brain’s cells.

If these microglia detect a virus, they produce interferon, which warns the neighbouring cells that a viral infection may be on the way and triggers the neuroimmune response, which keeps the infection at bay.

Response can damage the brain

However, the microglia response can be too strong, creating problems for the brain.

COVID-19 infection produces a similar response in the lungs. The most important problem is not the viral infection itself but the immune response in the form of a cytokine storm that floods part of the body with immune cells. Thus, a virus can trigger overactivation of the normal immune system in the lungs for COVID-19 or in the neuroimmune system for HSV-1 infection.

This destructive behaviour of the neuroimmune system is suspected to play a role in developing multiple sclerosis and Alzheimer’s disease.

Line Reinert compares the behaviour of microglia with firefighters who spray so much water on a house that the water causes more harm than the fire.

“An excessive cytokine storm kills the neurons and other cells, and this response does more damage than good. Our new study has clarified this and shows how the neuroimmune system prevents this from happening,” says Line Reinert.

Cells die to prevent overreaction

Line Reinert and colleagues studied various types of mice, infecting the brains with HSV-1 and then examining them under a microscope.

They examined how the neuroimmune system prevents the microglia from triggering a cytokine storm during a viral infection. The overactive microglia cells die to avoid doing more harm than good.

However, cells die in different ways, and the microglia undergo programmed cell death: apoptosis.

“A cell can die by exploding so all its constituents flow into the surrounding microenvironment. This is not ideal because it results in further cytokine storms and summons even more neuroimmune cells. However, microglia undergoing apoptosis shrivel up like tiny raisins, and this is how the neuroimmune system suppresses the immune response to prevent the neurons from being destroyed in controlling the viral infection,” explains Line Reinert.

Potential drugs to fight acute viral encephalitis

Further investigation also showed which signalling pathways the microglia use to balance protecting the brain and avoiding damage. The cGAS and STING proteins play important roles.

Genetically engineered mice lacking cGAS and STING died from HSV-1 infection. However, the mice died from the viral infection and not from excessive neuroimmune response. Line Reinert says that this shows how important cGAS and STING are for regulating the balance of the neuroimmune system.

Drugs are being developed today that can activate or inhibit cGAS and STING. According to Line Reinert, future research may show whether regulating cGAS and STING with drugs can help to protect the brain from a dangerous cytokine storm following an infection or boost the neuroimmune system.

In addition, drugs targeting cGAS and STING may also be used to treat other nervous system disorders that are not related to infection but may still result from excessive neuroimmune response.

“We have started new projects to investigate the immune mechanisms in developing other diseases such as COVID-19 and Alzheimer’s disease. We envision that we might eventually also inhibit or activate these molecular signalling pathways and thereby treat people with these diseases. However, this will be in the future, because we are still carrying out the basic scientific research,” says Line Reinert.

Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production” has been published in the Journal of Clinical Investigation. In 2018, the Novo Nordisk Foundation awarded a grant to Søren Riis Paludan for the project Novel Mechanisms of Early Defence against Virus Infections. In 2015, the Foundation awarded a grant to Trine Hyrup Mogensen for the project Identification of Novel Primary Immunodeficiencies Conferring Susceptibility to Viral Infections.

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